Neuroimaging studies indicate that a functionally interconnected set of brain structures, the so-called "default network" of resting brain function, maintains mental processes during passive rest such as when the mind wanders. Several chronic disease states characterized by cognitive dysfunction, such as schizophrenia and Alzheimer's disease (AD), are reported to display deficient down-regulation of default network activity when engaging in attention-demanding tasks. Failure to deactivate default activity is known to lead to acute performance errors and attentional lapses. The potential of manipulating default activity pharmacologically would thus open up a novel approach to improving cognition in these disease populations. A recent experiment in minimally deprived smokers suggests that enhanced attention by large- dose nicotine may be mediated by enhanced task-induced deactivation of the default network. The currently proposed project is designed to determine whether default network activity is modulated by nicotinic tone. Demonstrating such modulation and associated performance benefits by nicotinic ligands would open up a novel mechanism to improving attention, and would lay the groundwork for investigations on clinical benefits of this mechanism. Functional Magnetic Resonance Imaging will be employed to measure effects of transdermal nicotine and the nicotinic antagonist mecamylamine on default network activity during cognitive task performance. Both drugs will be tested in the same group of subjects, who will be scanned three times, once after receiving either drug and once after placebo. All participants will be non-smokers;default network modulation by nicotine in nicotine-naove individuals would demonstrate that the effect does not reflect reversal of a withdrawal state and provide the proof of concept needed for a clinical application. Nicotine is expected to aid task-induced deactivation of default activity, particularly under conditions that invited task- independent thought and attentional lapses. This effect is expected to be associated with enhanced performance. Mecamylamine, in contrast, is expected to weaken task-induced default deactivation, and this effect is expected to be associated with performance impairment and greater performance variability as seen in schizophrenia and AD. A state of low nicotinic receptor tone would thus model default dysregulation and specific performance deficits seen in these patient populations and suggest that it may be causal to these problems. Finally, nicotinic modulation of functional connectivity of default regions will be examined. Such connectivity has been shown to influence cognitive performance, and a strengthening by nicotine and weakening by mecamylamine may be another mechanism of performance modulation. Demonstration of robust effects of nicotinic receptor ligands on default network activity would not only motivate a broad range of future investigations on clinical applications of this mechanism but also provide an important neuroimaging test model in the search for novel nicotinic agonists with cognitive-enhancing potential. PUBLIC HEALTH RELEVANCE: Many disorders where attentional problems are a hallmark, such as Alzheimer's disease and schizophrenia, display abnormal regulation of the so-called default network of resting brain function that maintains internally directed thought when the mind is free to wander. These regions can be overactive or less readily deactivated with attention-demanding tasks, and excess activity is thought to impair performance. There is indication that nicotine may improve attention by aiding the deactivation of the default network, and this mechanism may be of therapeutic benefit for the above disease states. The current project aims at providing a proof of concept by demonstrating that nicotinic drugs modulate default network function.